Chemical process

ABSTRACT

A process for the preparation of the compound (I) or an acid addition salt thereof which comprises reacting a compound of formula (II), wherein R is an optionally substituted benzyl group under concomitant reduction and hydrogenolysis conditions, followed, if required, by isolation of the compound as an acid addition salt thereof.

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/EP01/03820 filed Apr. 4, 2001, which claims priority from GB0008179.4 filed Apr. 5, 2000.

The present invention relates to an improved process for preparing anintermediate for use in the synthesis of Cholecystokinin (CCK) agonists.

WO94/24149 describes a class of 1,5-benzodiazepine derivatives having anagonist action at the CCK-A receptor.

A particular interesting group of 1,5-benzodiazepine derivativesdescribed therein may be represented by the general formula (A)

The compounds of formula A are conveniently prepared from the 3-aminoderivative (I).

WO94/24149 teaches that such 3-amino-1,5-benzodiazepine derivatives maybe prepared by reduction of the corresponding phenylhydrazone and thepreparation of the compound of formula (I) by the reduction of thecorresponding phenylhydrazone (B), is specifically described inintermediate 11 therein.

Reduction of the hydrazone (B) to give the amine (I) also results in theformation of aniline. This is a highly toxic product, the generation ofwhich should be avoided if at all possible in a commercial process andthus there is a need to find an alternative synthesis to the primaryamine (I) which avoids the generation of aniline and provides therequired product in good yield.

We have now found that the required amine (I) can be prepared in highyield and without the consequential generation of toxic by products byconcomitant reduction and hydrogenolysis of the corresponding oxime(II), wherein R is an optionally substituted benzyl group.

Thus the present invention provides for a process for preparing theamine (I) by concomitant reduction and hydrogenolysis of the oxime (II)followed, if desired, by isolation of the compound as an acid additionsalt thereof.

The concomitant reduction and hydrogenolysis is conveniently carried outusing a Palladium catalyst e.g. Palladium on charcoal catalyst in thepresence of hydrogen or ammonium formate in a solvent such as an alkanole.g. ethanol, isopropanol or an aqueous ethanol, e.g. aqueous ethanol,or tetrahydrofuran

For the reaction the group R is conveniently benzyl or a substitutedbenzyl group e.g. p-methoxybenzyl or benzhydryl. Preferably R is benzyl

The oxime (II) may conveniently be prepared by reaction of theortho-phenylene diamine derivative (III)

with an activated derivative of the di-acid (IV), wherein R is anoptionally substituted benzyl group.

Conveniently, the activated derivative of the di acid (IV) is thecorresponding diacylhalide e.g. chloride and this is prepared in situ byreaction of the di-acid (IV) with an oxalyl halide e.g. oxalyl chloride.The reaction is conveniently carried out in an aprotic solvent such asan ester e.g. ethyl acetate, dichloromethane, toluene, or dimethoxyetheror mixtures thereof, and in the presence of dimethylformamide.

The di acid (IV) is conveniently prepared by reaction of a dialkylketomalonate e.g. diethyl ketomalonate with the correspondinghydroxylamine derivative RONH₂ in a solvent such as an alkanol orindustrial methylated spirits and in the presence of a base e.g.pyridine, or sodium hydroxide followed, if required, by reaction withaqueous sodium hydroxide.

The following examples, which are non-limiting, illustrate theinvention.

In the Examples the abbreviations EtOAc=ethyl acetate; MeOH=methanol,DMF=N,N-dimethylformamide; IPA=isopropyl alcohol; IMS=industrialmethylated spirits.

Intermediate 1 Diethyl 2-[(benzyloxy)imino]malonate

Di-ethylketomalonate (60 g) was added at 20° C. to a stirred suspensionof O-benzylhydroxylamine (57.8 g) in IMS (500 ml) containing pyridine(30 ml). The reaction was heated at 75° C. for 4 hr. The reaction wascooled and solvents removed under reduced pressure. The residue waspartitioned between EtOAc (500 ml) and water (300 ml) and the organiclayer separated, washed with water (250 ml) and dried over MgSO₄.Solvents were evaporated to give the title compound 95.3 g, as acolourless oil (99% th, ca 3% w/w residual EtOAc) which was used withoutfurther purification.

1H NMR (300 MHz, CDCl₃) 7.4 (m, 5H), 5.35 (s, 2H), 4.35 (m, 4H), 1.3 (m,6H).

Intermediate 2 Method A

2-[(benzyloxy)imino]malonic acid

To a solution of Intermediate 1 (40 g) in MeOH (80 ml) was added 2M NaOH(200 ml) over 20 mins. The reaction was stirred at room temperature for2 hr. MeOH was removed under reduced pressure and the residual solutionwas acidified to pH 2 by dropwise addition of conc.HCl (˜30 ml) whilecooling to maintain the temperature below 35° C. A thick white slurrywas formed which was diluted with water (50 ml) to aid mobility. Thesolids were collected by filtration, washed with chilled water (25 ml)and dried in vacuo at 55° C. to give the title compound as a white solid(17 g) found to contain ca.10% w/w residual inorganic salts. Correctedyield ˜45% th. Used without further purification.

1H NMR (300 MHz, D₂O) 7.4 (m, 5H), 5.2 (s, 2H)

Method B 2-[(Benzyloxy)imino]malonic acid

To a solution of sodium hydroxide (5.74 g) in water (50 ml) and IMS (80ml) was added benzylhydroxylamine hydrochloride (22.9 g). Diethylketomalonate (25 g,) was added and the mixture warmed to 60° C. andstirred for 4 h. The mixture was cooled to 30° C. and then added over˜10 minutes to a solution of sodium hydroxide (16.1 g) in water (180 ml)maintaining the internal temperature between 25-30° C. The mixture wasstirred at 25° C. for ˜1 h. This solution was added to a mixture ofconc. hydrochloric acid (50 ml) in ethyl acetate (160 ml) and water (20ml) at 10° C. The rate of addition is controlled to maintain theinternal temperature below 15° C. The mixture was allowed to warm to 25°C., and the phases were separated. The aqueous phase was extracted withethyl acetate (200 ml) and this wash was combined with the organicphase. The solution was concentrated to ˜100 ml by distillation underreduced pressure. Toluene (50 ml) was added and the mixture concentratedunder reduced pressure to ˜100 ml. Further toluene (150 ml) was addedand the mixture concentrated under reduced pressure to ˜100 ml andprecipitation of a white solid was observed. The solid was collected byfiltration and washed with toluene. The solid was dried in vacuo at 40°C. to give the title compound (24.4 g).

Intermediate 32-[-3-[(Benzyloxy)imino]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl)-N-isopropyl-N-phenylacetamideMethod A

Oxalyl chloride (38.3 g) was added dropwise (˜1 hr) to a stirredsuspension of Intermediate 2 (40 g, corrected for salt content to 31.4g) in EtOAc (200 ml) containing DMF (0.5 ml, 5 mol %). The mixture wasstirred at 25° C. for 0.5 hour then filtered through a pad of Dicalite,washing with EtOAc (40 ml) to give a clear yellow solution. The solutionwas added (˜5 mins) to a stirred slurry ofN-isopropyl-N-phenyl-2-(2-phenylaminophenylamino)-acetamide (50 g) inEtOAc (120 ml) at 25° C. The mixture was warmed to 60° C. and a darkpurple solution formed. After 1 hr, EtOAc (200 ml) was removed byatmospheric distillation. IPA (120 ml) and water (40 ml) were added andthe mixture distilled further to remove more solvent (80 ml). IPA (40ml) and water (40 ml) were added and a further amount of solvent wasdistilled out (80 ml). The reaction mixture was cooled to 25° C. over1.5 hr and the solids collected by filtration. The solids were washedwith IPA (2×120 ml), water (1×120 ml) and finally IPA again (1×40 ml)then dried in vacuo at 55° C. to give the title compound as a powder(56.6 g).

1H NMR (300 MHz, CDCl₃) 2:1 mixture of isomers about the oxime 7.6-6.95(m. 18H), 6.9 (t 1H), 5.3 (m, 2H), 4.95 (m, H), 4.65 (d, 0.33H), 4.4 (d,0.67H), 4.1 (d, 0.67H), 4.0 (d, 0.33H), 0.95 (m, 6H)

Method B

Oxalyl chloride (143 g) was added dropwise over ˜1 h to a stirredsolution of 2-[(benzyloxy)imino]malonic acid (123 g) in ethyl acetate(250 ml) containing N,N-dimethylformamide (1.2 g) at 25° C. Thehomogeneous mixture was stirred for 2 hr. The solution was added over ˜1h to a stirred slurry ofN-isopropyl-N-phenyl-2-(2-phenylamino)-acetamide (198 g) in ethylacetate (800 ml) at 60° C. The reaction mixture was stirred at 60° C.for at least 1.5 h. The mixture (suspension) was cooled to 30° C. andisopropanol (200 ml) was added and the suspension stirred overnight. Thesolid was collected by filtration, washing with isopropanol and dried at55° C. in vacuo to yield the title compound as a pale yellow solid (187g).

EXAMPLE 1(±)-2-(3-Amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo-[b][1,4]diazepen-1-yl)-N-isopropyl-N-phenylacetamideMethod A

To a stirred suspension of Intermediate 3 (3 g) and ammonium formate(2.08 g) in IMS (30 ml) and water (3 ml) was added 5% Pd/C (50% w/wwater) (0.25 g). The mixture was heated under a nitrogen atmosphere at60° C. overnight. The hot reaction mixture was filtered through Dicaliteto remove the catalyst. The catalyst was washed with hot IMS (60 ml) andfiltered. The filtrates were concentrated under reduced pressure to givethe title compound as a white solid (2.34 g).

Method B

2-[3-[(Benzyloxy)imino]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl)-N-isopropyl-N-phenylacetamide(10 g) was suspended in IMS (100 ml) with 5% Pd/C (50% wet) (1.5 g, 15%w/w) and heated at 70° C. for ˜6 hr under a hydrogen atmosphere at 5 barpressure. The mixture was cooled and THF (50 ml) was added. The mixturewas heated to reflux for 2 hours and filtered hot under nitrogen toremove the catalyst. The mixture was concentrated by distillation to ˜50ml with precipitation of the product. The solid is isolated byfiltration and washed with IMS (10 ml) and dried in vacuo at 55° C. toyield the title compound as a white solid (7.0 g).

¹H NMR (500 MHz, d₅-DMSO+D₂O) δ0.9 (m, 6H), 4.15 (d, J=12 Hz, 1H), 4.4(m, 1H), 4.7 (m, 1H), 4.9 (s, 1H), 6.9 (d, J=5 Hz, 1H), 7.2-7.6 (m,13H).

What is claimed is:
 1. A process for the preparation of the compound offormula (I)

or an acid addition salt thereof which comprises reacting a compound offormula (II)

 wherein R is benzyl or a substituted benzyl group under concomitantreduction and hydrogenolysis conditions, followed, if required, byisolation of the compound as an acid addition salt thereof.
 2. A processas claimed in claim 1 wherein the concomitant reduction andhydrogenolysis is carried out using a palladium catalyst.
 3. A processas claimed in claim 1 wherein the concomitant reduction andhydrogenolysis is carried out using hydrogen or ammonium formate.
 4. Aprocess as claimed in any of claims 1 wherein the compound of formula(II) has been prepared by reaction of the ortho phenylene diaminederivative (Ill) with an activated derivative of the di-acid (IV),

wherein R is benzyl or a substituted benzyl group.
 5. A process asclaimed in claim 4 wherein the activated derivative of the di-acid (IV)is the diacylchloride.
 6. A process as claimed in claim 1 wherein R isbenzyl.